Potential role of intratumor bacteria in mediating tumor resistance to the chemotherapeutic drug gemcitabine

Leore T. Geller; Michal Barzily-Rokni; Tal Danino; Oliver H. Jonas; Noam Shental; Deborah Nejman; Nancy Gavert; Yaara Zwang; Zachary A. Cooper; Kevin Shee; Christoph A. Thaiss; Alexandre Reuben; Jonathan Livny; Roi Avraham; Dennie T. Frederick; Matteo Ligorio; Kelly Chatman; Stephen E. Johnston; Carrie M. Mosher; Alexander Brandis; Garold Fuks; Candice Gurbatri; Vancheswaran Gopalakrishnan; Michael Kim; Mark W. Hurd; Matthew Katz; Jason Fleming; Anirban Maitra; David A. Smith; Matt Skalak; Jeffrey Bu; Monia Michaud; Sunia A. Trauger; Iris Barshack; Talia Golan; Judith Sandbank; Keith T. Flaherty; Anna Mandinova; Wendy S. Garrett; Sarah P. Thayer; Cristina R. Ferrone; Curtis Huttenhower; Sangeeta N. Bhatia; Dirk Gevers; Jennifer A. Wargo; Todd R. Golub; Ravid Straussman

doi:10.1126/science.aah5043

Potential role of intratumor bacteria in mediating tumor resistance to the chemotherapeutic drug gemcitabine

Leore T. Geller, Michal Barzily-Rokni, Tal Danino, Oliver H. Jonas, Noam Shental, Deborah Nejman, Nancy Gavert, Yaara Zwang, Zachary A. Cooper, Kevin Shee, Christoph A. Thaiss, Alexandre Reuben, Jonathan Livny, Roi Avraham, Dennie T. Frederick, Matteo Ligorio, Kelly Chatman, Stephen E. Johnston, Carrie M. Mosher, Alexander BrandisGarold Fuks, Candice Gurbatri, Vancheswaran Gopalakrishnan, Michael Kim, Mark W. Hurd, Matthew Katz, Jason Fleming, Anirban Maitra, David A. Smith, Matt Skalak, Jeffrey Bu, Monia Michaud, Sunia A. Trauger, Iris Barshack, Talia Golan, Judith Sandbank, Keith T. Flaherty, Anna Mandinova, Wendy S. Garrett, Sarah P. Thayer, Cristina R. Ferrone, Curtis Huttenhower, Sangeeta N. Bhatia, Dirk Gevers, Jennifer A. Wargo, Todd R. Golub, Ravid Straussman

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Abstract

Growing evidence suggests that microbes can influence the efficacy of cancer therapies. By studying colon cancer models, we found that bacteria can metabolize the chemotherapeutic drug gemcitabine (2′,2′-difluorodeoxycytidine) into its inactive form, 2′,2′-difluorodeoxyuridine. Metabolism was dependent on the expression of a long isoform of the bacterial enzyme cytidine deaminase (CDD_L), seen primarily in Gammaproteobacteria. In a colon cancer mouse model, gemcitabine resistance was induced by intratumor Gammaproteobacteria, dependent on bacterial CDD_L expression, and abrogated by cotreatment with the antibiotic ciprofloxacin. Gemcitabine is commonly used to treat pancreatic ductal adenocarcinoma (PDAC), and we hypothesized that intratumor bacteria might contribute to drug resistance of these tumors. Consistent with this possibility, we found that of the 113 human PDACs that were tested, 86 (76%) were positive for bacteria, mainly Gammaproteobacteria.

Original language	English
Pages (from-to)	1156-1160
Number of pages	5
Journal	Science
Volume	357
Issue number	6356
DOIs	https://doi.org/10.1126/science.aah5043
State	Published - 15 Sep 2017

Bibliographical note

Funding Information:
R.S. is funded by the Israel Science Foundation (grant no. 1877/14), the Moross Integrated Cancer Center, the Fabrikant-Morse Families Research Fund for Humanity, the Hymen T. Milgrom Trust, Rising Tide Foundation, the Dr. Dvora and Haim Teitelbaum Endowment Fund, the Tobias and Toni Gottesfeld Scholarship, and by A. Shashua, Israel. R.S. is the incumbent of the Roel C. Buck Career Development Chair. T.R.G. is funded by the Howard Hughes Medical Institute and by the U.S. National Cancer Institute (grant no. U54CA112962). C.H. is on the scientific advisory board of Evelo Biosciences. J.A.W. is a paid advisor for GlaxoSmithKline, Roche/ Genentech, Novartis, and Bristol-Myers Squibb.

Publisher Copyright:
© 2017, American Association for the Advancement of Science. All rights reserved.

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Geller, L. T., Barzily-Rokni, M., Danino, T., Jonas, O. H., Shental, N., Nejman, D., Gavert, N., Zwang, Y., Cooper, Z. A., Shee, K., Thaiss, C. A., Reuben, A., Livny, J., Avraham, R., Frederick, D. T., Ligorio, M., Chatman, K., Johnston, S. E., Mosher, C. M., ... Straussman, R. (2017). Potential role of intratumor bacteria in mediating tumor resistance to the chemotherapeutic drug gemcitabine. Science, 357(6356), 1156-1160. https://doi.org/10.1126/science.aah5043

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title = "Potential role of intratumor bacteria in mediating tumor resistance to the chemotherapeutic drug gemcitabine",

abstract = "Growing evidence suggests that microbes can influence the efficacy of cancer therapies. By studying colon cancer models, we found that bacteria can metabolize the chemotherapeutic drug gemcitabine (2′,2′-difluorodeoxycytidine) into its inactive form, 2′,2′-difluorodeoxyuridine. Metabolism was dependent on the expression of a long isoform of the bacterial enzyme cytidine deaminase (CDDL), seen primarily in Gammaproteobacteria. In a colon cancer mouse model, gemcitabine resistance was induced by intratumor Gammaproteobacteria, dependent on bacterial CDDL expression, and abrogated by cotreatment with the antibiotic ciprofloxacin. Gemcitabine is commonly used to treat pancreatic ductal adenocarcinoma (PDAC), and we hypothesized that intratumor bacteria might contribute to drug resistance of these tumors. Consistent with this possibility, we found that of the 113 human PDACs that were tested, 86 (76%) were positive for bacteria, mainly Gammaproteobacteria.",

author = "Geller, {Leore T.} and Michal Barzily-Rokni and Tal Danino and Jonas, {Oliver H.} and Noam Shental and Deborah Nejman and Nancy Gavert and Yaara Zwang and Cooper, {Zachary A.} and Kevin Shee and Thaiss, {Christoph A.} and Alexandre Reuben and Jonathan Livny and Roi Avraham and Frederick, {Dennie T.} and Matteo Ligorio and Kelly Chatman and Johnston, {Stephen E.} and Mosher, {Carrie M.} and Alexander Brandis and Garold Fuks and Candice Gurbatri and Vancheswaran Gopalakrishnan and Michael Kim and Hurd, {Mark W.} and Matthew Katz and Jason Fleming and Anirban Maitra and Smith, {David A.} and Matt Skalak and Jeffrey Bu and Monia Michaud and Trauger, {Sunia A.} and Iris Barshack and Talia Golan and Judith Sandbank and Flaherty, {Keith T.} and Anna Mandinova and Garrett, {Wendy S.} and Thayer, {Sarah P.} and Ferrone, {Cristina R.} and Curtis Huttenhower and Bhatia, {Sangeeta N.} and Dirk Gevers and Wargo, {Jennifer A.} and Golub, {Todd R.} and Ravid Straussman",

year = "2017",

month = sep,

day = "15",

doi = "10.1126/science.aah5043",

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Geller, LT, Barzily-Rokni, M, Danino, T, Jonas, OH, Shental, N, Nejman, D, Gavert, N, Zwang, Y, Cooper, ZA, Shee, K, Thaiss, CA, Reuben, A, Livny, J, Avraham, R, Frederick, DT, Ligorio, M, Chatman, K, Johnston, SE, Mosher, CM, Brandis, A, Fuks, G, Gurbatri, C, Gopalakrishnan, V, Kim, M, Hurd, MW, Katz, M, Fleming, J, Maitra, A, Smith, DA, Skalak, M, Bu, J, Michaud, M, Trauger, SA, Barshack, I, Golan, T, Sandbank, J, Flaherty, KT, Mandinova, A, Garrett, WS, Thayer, SP, Ferrone, CR, Huttenhower, C, Bhatia, SN, Gevers, D, Wargo, JA, Golub, TR & Straussman, R 2017, 'Potential role of intratumor bacteria in mediating tumor resistance to the chemotherapeutic drug gemcitabine', Science, vol. 357, no. 6356, pp. 1156-1160. https://doi.org/10.1126/science.aah5043

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T1 - Potential role of intratumor bacteria in mediating tumor resistance to the chemotherapeutic drug gemcitabine

AU - Geller, Leore T.

AU - Barzily-Rokni, Michal

AU - Danino, Tal

AU - Jonas, Oliver H.

AU - Shental, Noam

AU - Nejman, Deborah

AU - Gavert, Nancy

AU - Zwang, Yaara

AU - Cooper, Zachary A.

AU - Shee, Kevin

AU - Thaiss, Christoph A.

AU - Reuben, Alexandre

AU - Livny, Jonathan

AU - Avraham, Roi

AU - Frederick, Dennie T.

AU - Ligorio, Matteo

AU - Chatman, Kelly

AU - Johnston, Stephen E.

AU - Mosher, Carrie M.

AU - Brandis, Alexander

AU - Fuks, Garold

AU - Gurbatri, Candice

AU - Gopalakrishnan, Vancheswaran

AU - Kim, Michael

AU - Hurd, Mark W.

AU - Katz, Matthew

AU - Fleming, Jason

AU - Maitra, Anirban

AU - Smith, David A.

AU - Skalak, Matt

AU - Bu, Jeffrey

AU - Michaud, Monia

AU - Trauger, Sunia A.

AU - Barshack, Iris

AU - Golan, Talia

AU - Sandbank, Judith

AU - Flaherty, Keith T.

AU - Mandinova, Anna

AU - Garrett, Wendy S.

AU - Thayer, Sarah P.

AU - Ferrone, Cristina R.

AU - Huttenhower, Curtis

AU - Bhatia, Sangeeta N.

AU - Gevers, Dirk

AU - Wargo, Jennifer A.

AU - Golub, Todd R.

AU - Straussman, Ravid

PY - 2017/9/15

Y1 - 2017/9/15

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AB - Growing evidence suggests that microbes can influence the efficacy of cancer therapies. By studying colon cancer models, we found that bacteria can metabolize the chemotherapeutic drug gemcitabine (2′,2′-difluorodeoxycytidine) into its inactive form, 2′,2′-difluorodeoxyuridine. Metabolism was dependent on the expression of a long isoform of the bacterial enzyme cytidine deaminase (CDDL), seen primarily in Gammaproteobacteria. In a colon cancer mouse model, gemcitabine resistance was induced by intratumor Gammaproteobacteria, dependent on bacterial CDDL expression, and abrogated by cotreatment with the antibiotic ciprofloxacin. Gemcitabine is commonly used to treat pancreatic ductal adenocarcinoma (PDAC), and we hypothesized that intratumor bacteria might contribute to drug resistance of these tumors. Consistent with this possibility, we found that of the 113 human PDACs that were tested, 86 (76%) were positive for bacteria, mainly Gammaproteobacteria.

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Potential role of intratumor bacteria in mediating tumor resistance to the chemotherapeutic drug gemcitabine

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